LRP mediated cellular signaling events

低密度脂蛋白受体相关蛋白(LRP)是一种存在于大多数细胞表面的大型内源性受体，它与细胞外配体结合并靶向溶酶体进行降解。大多数LRP配体是在炎症和/或伤口修复过程中产生的，这一事实使我们推测LRP的功能可能超出了分解代谢的功能，并且这些配体中的某些配体与LRP的结合可能会产生细胞反应。在这方面，我们观察到LRP基因的重建成为这一应用的中心假设是，LRP在炎症和伤口修复过程中产生的分子的结合可以触发炎性细胞因子的产生，并通过趋化因子治疗改变动脉粥样硬化等炎症性疾病的进展。需要检验的具体假设是：1)某些配体与LRP相互作用以刺激炎症反应介质的产生，特定的胞浆分子(如蛋白激酶Calpha)与LRP的细胞质结构域相互作用并参与LRP介导的信号活动，以及3)LRP可调节巨噬细胞产生细胞因子，从而改变炎症疾病(如动脉粥样硬化)的进展。这些假说将在以下方面得到验证：1.确定LRP是否作为信号受体发挥作用，导致炎性细胞因子和趋化因子的分泌，并确定触发这一反应的配体。2.在小鼠模型中使用组织特异性LRP基因敲除来确定PKCalpha与LRP对巨噬细胞功能的贡献是否存在关联。

The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor present on the surface of most cell types, where it binds extracellular ligands and targets them to lysosomes for degradation The fact that most LRP ligands are generated during inflammation and/or wound repair processes led us to speculate that the function of LRP may extend beyond that of a catabolic one, and that association of certain of these ligands with LRP may generate a cellular response. In this regard, we have observed that reconstitution of the LRP gene into central hypothesis of this application is that binding of molecules generated during inflammation and wound repair of LRP can trigger the production of inflammatory cytokines and chemokines therapy altering the progression of inflammatory diseases such as atherosclerosis. The specific hypotheses to be tested are: 1) that the certain ligands interact with LRP to stimulate production of mediators of the inflammatory response, that specific cytosolic molecules, (e.g. protein kinase Calpha) interact with the cytoplasmic domain of LRP and participate in LRP- mediated signaling activities, and 3) that LRP can modulate cytokine production by macrophages, and thereby alter the progression of inflammatory diseases such as atherosclerosis. These hypothesis will be tested in the following aims: 1. Determine if LRP functions as a signaling receptor leading to secretion of inflammatory cytokines and chemokines, and identify ligands that trigger this response. 2. Determine if association of PKCalpha with LRP's contribution to macrophage function using tissue specific LRP knockouts in a mouse model.